Acute myeloid leukemia medical therapy
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The mainstay therapy from acute myeloid leukemia is chemotherapy and usually includes a combination of daunorubicin, cytarabine and etoposide or mitoxantrone and anabolic steroids. Supportive care includes intravenous nutricion, antimycrobial therapy, and replacement of blood products.
Treatment of acute myeloid leukemia consists primarily of chemotherapy and is divided into two phases: induction and postremission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. Maintenance therapy involving targeted therapy is used in some situations. Specific treatment plans may be used, depending on the type of leukemia that has been diagnosed. Many different chemotherapeutic plans are available for the treatment of acute myeloid leukemia. Overall, the strategy is to control bone marrow and systemic (whole-body) disease while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission (lessening of the disease) and a lower risk of disease resistance. Consolidation or "maintenance" treatments may be given to prevent disease recurrence once remission has been achieved. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with added drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase. It is important for the patient to understand the treatment that is being given and the decision-making process behind the choice.
- Initial treatment of acute myeloid leukemia usually begins with induction chemotherapy using a combination of drugs such as daunorubicin (DNR), cytarabine (ara-C), idarubicin, thioguanine, etoposide, or mitoxantrone and anabolic steroids.
All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin). Other alternatives, including high-dose ara-C alone, may also be used. Because of the toxic effects of therapy, including myelosuppression and an increased risk of infection, induction chemotherapy may not offered to the very elderly. Induction chemotherapy usually requires a hospitalization of about 1 month to receive the chemotherapy and recover from its side effects.
Induction chemotherapy is known as "7 and 3" because the cytarabine is given as a continuous IV infusion for seven consecutive days, while the anthracycline is given for three consecutive days as an IV push. Up to 70% of patients will achieve a remission with this protocol.
The M3 subtype of acute myeloid leukemia, also known as acute promyelocytic leukemia, is almost universally treated with the drug ATRA (all-trans-retinoic acid) in addition to induction chemotherapy. Care must be taken to prevent disseminated intravascular coagulation (DIC), complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. APL is eminently curable with well-documented treatment protocols.
The goal of the induction phase is to reach a complete remission. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected with available diagnostic methods (i.e., <5% leukemic cells remain in the bone marrow). Complete remission is obtained in about 50%–75% of newly diagnosed adults, although this may vary based on the prognostic factors described above.
The durability of remission depends on the prognostic features of the original leukemia. In general, all remissions will fail without consolidation (post-remission) chemotherapy, and consolidation has become an important component of treatment.
Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further postremission or consolidation therapy is given, almost all patients will eventually relapse. Therefore, more therapy is necessary to eliminate non-detectable disease and prevent relapse — that is, to achieve a cure.
The specific type of postremission therapy is individualized based on a patient's prognostic factors (see above) and general health. For good-prognosis leukemias (i.e. inv(16), t(8;21), and t(15;17)), patients will typically undergo an additional 3–5 courses of intensive chemotherapy, known as consolidation chemotherapy. For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related acute myeloid leukemia), allogeneic stem cell transplantation is usually recommended if the patient is able to tolerate a transplant and has a suitable donor. The best postremission therapy for intermediate-risk acute myeloid leukemia (normal cytogenetics or cytogenetic changes not falling into good-risk or high-risk groups) is less clear and depends on the specific situation, including the age and overall health of the patient, the patient's personal values, and whether a suitable stem cell donor is available.
If, however, the acute myeloid leukemia patient has resistant disease (about 15%) or relapses (about 70%), second remissions sometimes are achieved by treating them with:
- Conventional induction chemotherapy
- High-dose ara-C (HDAC), with/without other drugs
- Etoposide or other single chemotherapeutic agents
Elderly acute myeloid leukemia patients have special treatment concerns. They may be less able to tolerate the septicemia (blood poisoning) associated with granulocytopenia, and they often have higher rates of myelodysplastic syndromes. Individuals who are over age 75 or who have significant medical conditions can be treated effectively with low-dose ara-C. High-dose post-induction chemotherapy is unlikely to be tolerated by elderly patients.
Until recently, the treatment plans and responses of children with acute myeloid leukemia did not differ much from those of adults. Yet new, more intensive induction and consolidation treatments have resulted in higher remission rates and prolonged survivals. Many induction trials have produced good results using combinations of cytarabine (ara-C) plus an anthracycline (e.g., daunorubicin, doxorubicin). In children under 3 years of age, the anthracycline used for induction should be chosen with care, since doxorubicin produces more toxicity and related deaths than daunorubicin.
Consolidation therapy is complex, but it should include at least two courses of high-dose ara-C (HDAC). Children who have hyperleukocytosis (too many white blood cells), especially monocytic M5 leukemia, have a poor prognosis.
Relapsed acute myeloid leukemia
Despite aggressive therapy, however, only 20%–30% of patients enjoy long-term disease-free survival. For patients with relapsed acute myeloid leukemia, the only proven potentially curative therapy is a stem cell transplant, if one has not already been performed. In 2000, Mylotarg (gemtuzumab ozogamicin) was approved in the United States for patients aged more than 60 years with relapsed acute myeloid leukemia who are not candidates for high-dose chemotherapy.
Patients with relapsed acute myeloid leukemia who are not candidates for stem cell transplantion, or who have relapsed after a stem cell transplant, should be strongly considered for enrollment in a clinical trial, as conventional treatment options are limited. Agents under investigation include cytotoxic drugs such as clofarabine as well as targeted therapies such as farnesyl transferase inhibitors, decitabine, and inhibitors of MDR1 (multidrug-resistance protein). Since treatment options for relapsed acute myeloid leukemia are so limited, another option which may be offered is palliative care.
For relapsed acute promyelocytic leukemia (APL), arsenic trioxide has been tested in trials and approved by the Food and Drug Administration. Like ATRA, arsenic trioxide does not work with other subtypes of acute myeloid leukemia.
Follow-up therapy for such patients may involve:
- Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients who have prolonged granulocytopenia; that is too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
- Injection with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), which may help to shorten the period of granulocytopenia that results from induction therapy
- Transfusions with red blood cells and platelets
Patients with newly diagnosed disease also may be considered for stem cell transplantation (SCT), either from the bone marrow or other sources. Allogeneic bone marrow transplant (alloBMT) is reserved primarily for patients under 55 years of age who have a compatible family donor. Approximately half of newly diagnosed acute myeloid leukemia patients are in this age group, with 75% achieving a complete remission (CR) after induction and consolidation therapy. Allogeneic bone marrow transplant is available for about 15% of all patients with acute myeloid leukemia. Unfortunately, it is estimated that only 7% of all acute myeloid leukemia patients will be cured using this procedure.
People who receive stem cell transplantation (SCT, alloBMT) require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.
Novel FDA-Approved Agents
In general, these recent FDA approvals largely stem from the identification and characterization of unique molecular subtypes. The years 2017 and 2018 were landmark years in AML, as 5 new therapies were brought to the market after a 40-year period of stagnation.
- Target: The target of midostaurin is the FLT3 receptor tyrosine kinase. With regards to the pre-leukemic evolution of the hematopoietic stem cell, the FLT3 mutation is one of the late driver mutations in AML. The FLT3 mutation occurs in about 30% of cytogenetically normal AML.
- Mechanism of action: Midostaurin is a multikinase inhibitor that inhibits FLT3 receptor signaling and cell proliferation. Importantly it also inhibits KIT, VEGFR2, and PDGFRa/b. It is therefore non-specific and thus has various adverse effects.
- Clinical trial data: In the midostaurin trial, also known as CALGB 10603 or the RATIFY alliance trial, 717 patients were randomized to either standard chemotherapy plus midostaurin or standard chemotherapy plus placebo. Patients were stratified based on FLT3 mutation status (namely, tyrosine kinase domain mutation or internal tandem duplication, with either high allelic ratio or low allelic ratio). Patients also received midostaurin maintenance if they were in remission after consolidation. Primary endpoint was overall survival. There improvement in median overall survival and event-free survival. The beneficial effect was seen across all subgroups stratified by FLT3 status.
- FDA approval: It is FDA approved for newly diagnosed AML with a FLT3 mutation, at a dose of 50mg PO twice daily on days 8-21, as well as during consolidation at a dose of 50mg PO twice daily on days 8-21 alongside high-dose cytarabine. It is also used as maintenance therapy at a dose of 50mg PO twice daily for 12 months.
- Adverse effects: Nausea, hypocalcemia, neutropenic fever, increased ALT, mucositis, vomiting, headache
- Target: Enasidenib targets the mutant isocitrate dehydrogenase 2 (IDH2) enzyme. The IDH2 mutation is a early mutation in the pre-leukemic evolution of the hematopoietic stem cell. The IDH2 mutation occurs in about 12-15% of patients with AML and is more commonly found in cytogenetically normal AML.
- Mechanism: Under normal conditions, the IDH enzyme catalyzes the reaction of isocitrate to alpha-ketoglutarate, and this reaction leads to the generation of reductive bioequivalents in the form of NADPH, which combats oxidative stress. However, in patients with the IDH2 mutation, this mutation confers neomorphic enzyme activity that leads to generation of the oncometabolite 2-hydroxyglutarate. Through a variety of epigenetic mechanisms, this leads to differentiation arrest. Enasidenib, or AG-221, is an oral selective inhibitor of the mutant IDH2. Enasidenib can be thought of a differentiation agent, similar to all-trans retinoic acid in acute promyelocytic leukemia.
- Clinical trial data: The trial that led to the approval of this agent was a first-in-human phase 1/2 trial that assessed the maximally tolerated dose, safety, and efficacy in patients with IDH2-mutant AML. Enasidenib 100mg PO daily was selected for the expansion phase, and continuous daily treatment was well tolerated. Results showed that, with each treatment cycle, there was an increasing proportion of patients who achieved complete remission. Overall response rate was 40% and median response duration was 5.8 months. Complete remission rate was 19%, and in the 19% of patients who achieved complete remission, the overall survival was 19 months. Median overall survival was 9.3 months.
- FDA approval: The FDA indication is for relapsed/refractory AML with IDH2 mutation at a dose of 100mg PO daily, administered continuously until unacceptable toxicity or disease progression. It should be given for at least 6 months.
- Adverse effects: Differentiation syndrome (to any degree of severity) occurs in 10% of patients. However, only 7% of patients develop grade 3 or higher differentiation syndrome. This syndrome includes edema, weight gain, shortness of breath. During the initial period after giving enasidenib, the white count actually rises and some may mistake this as disease progression, but this is actually pseudoprogression. Indirect hyperbili occurs in 12% patients. Nausea is common.
- Liposomal daunorubicin/cytarabine (CPX-351):
- Target: This agent targets DNA replication.
- Mechanism of action: CPX-351 is a dual-drug liposomal formulation that contains cytarabine and daunorubicin in a 5:1 molar ratio. Cytarabine is a nucleoside analog, and daunorubicin is an anthracycline that inhibits topoisomerase II and intercalates into DNA. The liposomal formulation helps deliver these cytotoxic agents into leukemia cells to a greater extent than normal cells. The liposome allows for persistent exposure of the drugs in the bone marrow.
- Clinical trial data: This was an open-label phase III trial consisting of 309 patients who were randomized to receive either CPX-351 or standard cytarabine/anthracycline chemotherapy for both induction and consolidation. The liposomal dose of cytarabine was 100mg/m2 and dose of daunorubicin was 44mg/m2, and this was given on days 1, 3, and 5 of induction. The liposomal formulation improved median overall survival compared to standard chemotherapy (9.5 months vs. 5.9 months). Liposomal daunorubicin/cytarabine also improved the overall remission rate compared to standard chemotherapy (47% vs. 33%). The safety profile was similar. Following the FDA approval, the European Commission recently approved in September 2018.
- FDA approval: This is FDA approved for newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). For cycle 1 of induction, it is given on days 1, 3, and 5. For cycle 2 of induction if needed, it is given on days 1 and 3. For consolidation, there is a 35% dose reduction.
- Adverse effects: hemorrhage, neutropenic fever, rash, edema, copper toxicity, cardiac toxicity
- Gemtuzumab ozogamicin:
- Target: This agent targets CD33, a protein expressed on the surface of 85-90% of myeloid cells.
- Mechanism of action: Gemtuzumab ozogamycin is an antibody-drug conjugate consisting of anti-CD33 plus the caliceamicin derivative ozogamicin. After internalization of the antibody-drug conjugate, ozogamicin causes DNA strand scission in the leukemia cells.
- Clinical trial data: The original trial for gemtuzumab ozogamycin used a dose of 9mg/m2. There was a 26% complete remission rate with the initial 9mg/m2 dose. However, gemtuzumab ozogamycin was taken off the market in 2010 due to safety and efficacy concerns, then reintroduced a lower dose and specifically for use in CD33-positive AML, based on the ALFA-0701 trial, a randomized phase III study of about 280 patients with de novo AML. In this trial, a low dose of fractionated gemtuzumab ozogamycin was used (3mg/m2 on days 1, 4, and 7), given the hematologic toxicity and veno-occlusive disease risk with 9mg/m2). The total induction dose was 9mg/m2 (since there were 3 doses of 3mg/m2), but the key difference was the fractionation of the regimen. The experimental group also received gemtuzumab ozogamycin on day 1 of each of 2 consolidation cycles so the total dose was 15mg/m2. The results showed 81% complete remission rate compared to 75% for standard chemotherapy. The beneficial effect was not restricted to any particular subgroup, though patients with the FLT3 mutation benefited the most.
- FDA approval: The FDA approval is for both newly diagnosed CD33-positive AML and relapsed/refractory AML. It is used during induction and during consolidation and continuation. It can be used in combination with standard chemotherapy or as monotherapy. We now give fractionated doses which allows for a higher total dose of gemtuzumab ozogamycin to be delivered while minimizing toxicity.
- Adverse effects: These include delayed platelet count recovery (thrombocytopenia) and veno-occlusive disease which is due to the ozogamycin component.
- Target: Ivosidenib targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. The IDH1 mutation is a early mutation in the pre-leukemic evolution of the hematopoietic stem cell. The IDH1 mutation occurs in about 6-10% of patients with AML.
- Mechanism of action:]: Ivosidenib or AG120 is an oral mutant IDH1 inhibitor. Its mechanism parallels that of enasidenib. Ivosidenib prevents production of the oncometabolite 2-hydroxyglutarate and leads to differentiation of cells.
- Clinical trial data: This was a phase 1 open-label dose-escalation and dose-expansion study. In this trial, 179 patients with relapsed/refractory AML and IDH1 mutation were treated with ivosidenib 500mg PO daily. Treatment with ivosidenib resulted in a low frequency of grade 3 or higher adverse events (QT prolongation in 8% of patients and differentiation syndrome in 4% of patients). Leukocytosis also occurred after initiation of treatment, similar to enasidenib. The efficacy outcomes for ivosidenib were very similar to enasidenib. The overall response rate was 41%. The rate of composite complete remission was 30%, and the rate of complete remission was 21%. The median duration of response was in the range of 6-9 months. Transfusion independence was achieved in 35% of patients. The IDH1 mutant clone was eradicated in 21% of patients.
- FDA approval: Ivosidenib 500mg PO daily is approved for relapsed/refractory AML with the IDH1 mutation. Treatment should continue for at least 6 months to allow response.
- Adverse effects: QT prolongation (occurs in in 8% of patients), differentiation syndrome (edema, weight gain, shortness of breath), hyperleukocytosis
Replacement of Blood Products
Indications for blood products replacement include:
- Hemoglobin concentration is lower than 7-8 g/d or higher if the patient has cardiovascular and pulmonary co-morbidities - packed red blood cells are given.
- Platelet count is lower than 10,000-20,000/µL - platelets are transfused
- In patients with gastrointestinal or pulmonary bleeding transfusions are done to maintain a platelet count of more than 50,000/µL.
- Patients with CNS hemorrhage should have transfusions to maintain a count of more than 100,000/µL.
- Prolonged prothrombin time - fresh frozen plasma
- Low fibrinogen levels - cryoprecipitate.
- Neutropenic diet - no fresh fruits, no fresh vegetables
- All foods should be cooked well including meat.
Drugs Approved for acute lymphoblastic leukemia
The following pharmaclogic agents have been aproved for the treatment of acute myeloid leukemia:
- Arsenic Trioxide
- Daunorubicin Hydrochloride
- Doxorubicin Hydrochloride
- Idarubicin Hydrochloride
- Mitoxantrone Hydrochloride
- Arsenic Trioxide
- Vincristine Sulfate
Drug Combinations Used in acute myeloid leukemia
Chemotherapy is often given as a combination of drugs called ADE
- Drugs in the ADE combination:
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